When functioning normally, the human colon absorbs about 99% of the water entering its lumen, which represents about 2 liters of water per day. The colon has the capacity to absorb up to an additional 4 liters of water. However, above 6 liters of water per day, its capacity for absorption is saturated, and diarrhea develops.
Diarrhea is a common problem (worldwide, about two billion cases each year) which is characterized by stools of liquid or soft consistency, more bulky and frequent than usual (more than 3 bowel movements per day). In extreme cases, more than 20 liters of fluid can be lost per day.
Diarrhea is not a disease, but a symptom. Its commonest cause is ingestion of contaminated water or food; in that case it lasts one or two days without requiring treatment. However, diarrhea itself can cause dehydration that can prove fatal, especially in an infant, where a weight loss exceeding 10% is a hospital emergency. According to the World Health Organization, diarrhea is the second commonest cause of infant mortality in third world countries, and is responsible for 18% of deaths of children under 5 years (Bryce et al., Lancet, 2005, 365: 1147-1152).
Dehydration caused by diarrhea occurs when the losses of fluid are not compensated. In the normal situation, it is in the colon that water is removed from the stool. The phenomena of reabsorption of the water contained in ingested matter occur at the level of the colonic cells by a combination of active and passive transport of water and electrolytes. At the level of the crypts of the invaginations of the colonic epithelium, there is secretion of water from the blood to the external environment. These two phenomena compensate one another in a person in good health and are able to maintain appropriate hydration of the stool, which promotes intestinal transit and improves the conditions of circulation of the molecules.
There are many possible causes of diarrhea, including diarrhea of infectious origin induced by a viral, bacterial or parasitic pathogen and noninfectious diarrhea, such as diarrhea induced by food intolerance, a fatty diet, alcohol, a psychological factor, administration of a medicinal product, administration of a therapeutic procedure, diarrhea associated with a disease or with a clinical condition, or diarrhea associated with drug withdrawal.
Depending on the duration of the symptoms, a distinction is made between acute diarrhea and chronic diarrhea, the symptoms of which last less than two weeks and at least two weeks, respectively.
A classical medication for the treatment of diarrhea is for example loperamide, which acts both by stimulating the absorption of water and electrolytes, and by slowing the transit time. However, slowing of the transit time can be problematic in severe infections of the Salmonella, Shigella or Clostridium difficile type, since the pathogenic bacterium remains in the intestine for a long time.
Probiotics represent an interesting alternative in the treatment and/or prevention of diarrhea. The probiotics most used for this indication are the lactic bacteria. The probiotics are then generally described as having a beneficial action on the immune system and on the equilibrium of the intestinal flora.
Other studies have tried to identify new targets for the treatment or prevention of diarrhea. Thus, document WO 2004/028480 describes compounds of the thiazolidinone type for lowering the effectiveness of transport of chloride ions by the CFTR protein (Cystic Fibrosis Transmembrane Conductance Regulator) and use thereof in the treatment of secretory diarrhea. Bradford et al. (Am. J. Physiol. Gastrointes. Liver Physiol., 2009, 296: G886-G898) have examined means for treating problems of intestinal obstruction and dehydration in patients with mucoviscidosis (in which there is altered expression of CFTR).
Moreover, it has been described that the partial or complete loss of the NHE3 protein (Sodium Hydrogen Exchanger 3) in mice with mucoviscidosis reduced the incidence of intestinal obstructions, notably by increasing intestinal fluidity, and it was concluded that NHE3 is a potential target for regulating the fluidity of the intestinal tract in patients with mucoviscidosis and with altered expression of CFTR.
Therefore, there is still a need for new strategies for treating and/or preventing diarrhea.